Physiology of Normal Blood Glucose Regulation

The metabolic fate of ingested glucose is determined by the interplay of multiple hormones. Insulin is of major importance in this homeostasis, but glucagon, glucocorticoids, catecholamines, and growth hormone also have significant effects that are interactive with insulin. Glucose ingested with a meal or derived from the digestion of other dietary carbohydrates is rapidly absorbed by the small intestine. It is carried first to the liver by the portal vein, where a substantial portion (30-70%) is removed; the remainder enters the peripheral circulation, where regulated insulin secretion and target tissue responses to insulin contribute to glucose clearance and control of blood glucose levels (Figure 1).

Following a meal, insulin is secreted from pancreatic ft cells in response to increased circulating glucose concentrations. This direct effect of glucose on ft cells is augmented by neural (vagal) and hormonal factors of intestinal origin (e.g., glucose-dependent insulinotropic peptide, cholecystokinin, and glucagon-like peptide 1), such that the insulin secretory response to oral glucose greatly exceeds the response to an equivalent intravenous glucose infusion.

The overall effect of the increase in insulin levels in parallel with increased glucose entry to the circulation is promotion of the net removal of glucose by the liver and stimulation of glucose transport into muscle and adipose tissue, where it is consumed as a metabolic fuel or stored. Insulin also inhibits the catabolism of the alternative energy sources, fat and protein. This is an appropriate response to the abundance of circulating nutrients that occurs after meals. During fasting, insulin levels are low, these processes are reversed, and stored fuel is made available to all tissues.

Liver Glucose enters the liver by facilitated (carrier-mediated) diffusion driven by the concentration gradient that exists in the fed state. A portion of the glucose taken up by the liver is metabolized via glycolytic pathways to produce ATP. A substantial amount is transformed into glycogen and stored. The maximal storage capacity of the liver is approximately 100 g glycogen (400kcal). The specific molecular effects of insulin in the fed state lead to altered activities of enzymes that trap glucose inside the hepatocyte, promote glycolysis, and enhance glycogen synthesis (Figure 1). Insulin also inhibits enzymes important for both glycogenolysis and gluconeogenesis and thus shuts off hepatic glucose production. A portion of the glucose entering the liver is converted into triglyceride and exported to the adipocyte for storage.

Skeletal muscle In skeletal muscle, insulin directly stimulates glucose uptake, which is the rate-limiting step for muscle clearance of glucose. This appears to occur predominantly by causing the rapid translocation of glucose transporters (in particular the Glut-4 transporter) from an as yet undefined intracellular site to the muscle cell surface. Insulin also stimulates glycolysis and the net formation of glycogen in muscle. Even at low insulin concentrations, however, a rise in ambient glucose stimulates substantial glucose clearance by muscle, probably via the Glut-1 transporter. Glycogen stores in muscle (500-600 g glycogen in a 70 kg human) serve as a rapidly mobilized energy source during exercise but do not directly support blood glucose concentrations in the fasted state because muscle lacks the enzyme glucose-6-phosphatase, which is needed for release of free glucose to the circulation. Insulin-stimulated amino acid entry into muscle enhances insulin stimulatory effects on protein synthesis and decreases the availability of circulating amino acids as substrates for hepatic gluconeogenesis. Muscle proteolysis, which yields amino acid precursors that contribute to hepatic gluconeogenesis in the fasted state, is inhibited by insulin.

Liver

Small intestine

Liver

Skeletal muscle

Figure 1 Insulin effects on glucose homeostasis in the fed state.

Carbohydrates —Glucose r Portal glucose J

^ Systemic glucose j

Gl secretagogues/Neural factors

Pancreatic islets

Skeletal muscle

Figure 1 Insulin effects on glucose homeostasis in the fed state.

Carbohydrates —Glucose

Gl secretagogues/Neural factors r Portal glucose J

^ Systemic glucose j

Pancreatic islets

Adipose tissue

Insulin

Insulin

Adipose tissue

Adipose tissue In adipose tissue, insulin stimulates glucose uptake via the Glut-4 transporter, providing substrate for energy generation and glycerol synthesis. Even more important effects of insulin in adipose tissue are inhibition of lipolysis and stimulation of FFA uptake and triglyceride synthesis. This limits the availability of fat-derived fuels for other tissues and indirectly contributes to the lowering of blood glucose by favoring glucose utilization in multiple tissues.

From this brief overview, it can be seen that the rise in insulin following a meal has multiple tissue-specific actions that serve to lower blood glucose, prevent hyperglycemia, and inhibit the mobilization of alternative metabolic fuels. Many of the metabolic abnormalities that develop acutely in uncontrolled diabetes can be explained by the loss of these actions of insulin.

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